分子靶标与动态分子影像预测鼻咽癌放疗预后的相关机制研究

Prognostic factors of nasopharyngeal carcinoma (NPC) radiotherapy is insufficient. The EB virus is an important biological factor of disease of nasopharyngeal carcinoma, EB virus latent infection in nasopharyngeal carcinoma cells can produce genetic latent membrane protein 1 ( LMP1 )，which can be detected from the part of pathological tissue, is a recognized Oncogene in nasopharyngeal carcinoma, it can produce a variety of pathological effects through the activation of NF-κ B, AP-1 and JAK/STAT signaling pathways. However,it is still not clear that how LMP1 is related with nasopharyngeal carcinoma cell migration, angiogenesis, hypoxia, metabolic. And FDG PET/CT, as the representative of the functional imaging, have a relationship with metabolism, angiogenesis, hypoxia of the while lesion. But what is the biological mechaniam is still not certain, especially in NPC. Through the reported in the literature and our previous study, we hypothesis: LMP1 expression and the dynamical parameters of functional imaging should distinguish different individuals for nasopharyngeal carcinoma.The ones which the level of EB virus infection is higher,the tumor angiogenesis and metabolic ability are more strong, should be apt to destroy the connection between tumor cells, and provide the transfer condition. So the risk of metastases is higher. On the contrary, when the nasopharyngeal carcinoma cell hypoxia level is higher, the sensitivity to radiotherapy in the treatment of cancer should be lower and risk of recurrence. The project is to explore the mechanism of the prognosis and prediction of radiotherapy between molecular targets and dynamical molecular imaging of the construction of a new molecular model for predicting the curative effect and prognosis of nasopharyngeal carcinoma.

预测鼻咽癌放疗预后的因素仍存在不足。已知鼻咽癌细胞中潜伏感染的EB病毒能诱导潜伏膜蛋白1(LMP1),其能从肿瘤病理组织中检测，是一种被公认的癌基因，在鼻咽癌中它能通过激活NF-κB、AP-1及JAK/STAT等信号通路产生多种病理效应。然而，其与癌细胞的转移、血管生成、乏氧、代谢等关系未完全明确。而FDG PET/CT为代表的功能影像反映肿瘤整体的代谢、血管生成、乏氧等病理过程的分子机制也尚未明朗。通过文献报道及我们之前的研究，我们推测：LMP1及其下游通路的表达及功能影像动态参数将区分不同鼻咽癌个体，对于更高的EB病毒感染水平者，破坏了肿瘤细胞之间的连接，同时肿瘤血管生成、代谢能力更强，其肿瘤转移的风险高；反之，鼻咽癌细胞乏氧水平高者，放疗敏感性较低，肿瘤治疗中复发风险更大。项目通过探索局部分子靶标和动态的整体分子影像之间的关系及预测放疗预后的机制，构建一种新的分子模型预测鼻咽癌预后。

复发和转移是鼻咽癌治疗失败的主要原因，因此建立有效的鼻咽癌复发转移预测模型对鼻咽癌的治疗意义重大。EB病毒通过激活一系列的信号通路参与鼻咽癌的发生发展，PET/CT在鼻咽癌的诊断和疗效预测方面也发挥重要作用，本研究拟通过将EBVDNA及其激活的下游信号通路分子结合PET/CT相关参数建立鼻咽癌预测模型。本研究通过优化EBVDNA荧光定量方法，实现EBVDNA定量的标准化和国际溯源，同时运用该标准化方法发现EBVDNA载量与鼻咽癌复发和转移有关。本研究还发现PET/CT参数SUVmax在鼻咽癌治疗前、治疗结束后能预测患者总生存时间，并且与EBVDNA正相关，两者结合能更好地预测鼻咽癌预后。本研究还发现EB病毒潜伏膜蛋白1（LMP1）新的下游靶基因细胞周期相关转录因子（E2F）和干扰素调节因子1（Interferon Regulatory Factor 1，IRF1），E2F通过作用CCT3促进鼻咽癌的凋亡，IRF1通过调控PD-L1介导鼻咽癌免疫逃逸。E2F与IRF1有望成为鼻咽癌新的预后预测标志物。通过本课题研究，初步确定有效的鼻咽癌预后预测模型，对提高我国鼻咽癌治疗领域的水平有着重要的社会意义和经济价值。